Cancers doi: 10.20517/2394-5079.2025.58

Authors: Zhao Ruan,Xuedan Sun

Metabolic reprogramming is a fundamental mechanism through which tumor cells reshape their energy metabolism to sustain rapid proliferation. It facilitates malignant growth by reprogramming key pathways, including glycolysis and amino acid metabolism. The tumor microenvironment (TME) is composed of tumor cells, stromal cells, and immune cells. The characteristics of hypoxia, acidity, and nutrient deficiency are mainly driven by the metabolic products and cytokines secreted by tumor cells. This metabolic pressure not only inhibits the functions of immune cells, but also further enhances immune evasion through nutrient competition. Targeting metabolic reprogramming can reverse immunosuppression within the TME and enhance the response to immunotherapy. This article systematically reviews the regulatory mechanisms of metabolic reprogramming in hepatocellular carcinoma and its impact on the TME, while also exploring therapeutic strategies based on metabolic interventions.

Cancers doi: 10.20517/2394-5079.2025.58

Authors: Zhao Ruan,Xuedan Sun

Metabolic reprogramming is a fundamental mechanism through which tumor cells reshape their energy metabolism to sustain rapid proliferation. It facilitates malignant growth by reprogramming key pathways, including glycolysis and amino acid metabolism. The tumor microenvironment (TME) is composed of tumor cells, stromal cells, and immune cells. The characteristics of hypoxia, acidity, and nutrient deficiency are mainly driven by the metabolic products and cytokines secreted by tumor cells. This metabolic pressure not only inhibits the functions of immune cells, but also further enhances immune evasion through nutrient competition. Targeting metabolic reprogramming can reverse immunosuppression within the TME and enhance the response to immunotherapy. This article systematically reviews the regulatory mechanisms of metabolic reprogramming in hepatocellular carcinoma and its impact on the TME, while also exploring therapeutic strategies based on metabolic interventions.

Cancers doi: 10.20517/2394-5079.2025.39

Authors: Ludovico Abenavoli,Maria Luisa Gambardella,Eugenia Passante,Giuseppe La Torre,Caterina Battaglia,Francesco Manti,Domenico Console,Francesco Luzza,Domenico Laganà

Hepatocellular carcinoma (HCC) remains a significant global health issue, linked to chronic liver diseases such as viral hepatitis, cirrhosis, and metabolic dysfunction-related steatohepatitis. Early, accurate diagnosis is vital for treatment, but many cases are diagnosed at advanced stage. Contrast-enhanced ultrasound (CEUS) is a valuable, radiation-free tool for real-time liver lesion assessment with high accuracy. This review examines the growing role of ultrasound and CEUS in diagnosing, monitoring, and post-treatment care of HCC. CEUS has sensitivity and specificity similar to computed tomography and magnetic resonance imaging, especially for nodules ≥ 1 cm, and helps clarify uncertain Liver Imaging Reporting and Data System findings. Dynamic CEUS improves diagnosis by allowing microvascular perfusion measurement. Artificial intelligence (AI) and machine learning integration promises automated lesion classification and better consistency. CEUS is especially useful in outpatient and resource-limited settings, enabling quick decision-making and reducing delays. Meta-analyses and studies support CEUS for initial detection and post-treatment follow-up. As advanced ultrasound becomes more accessible, CEUS can be more widely used in hepatology. Future steps include standard protocols, clinician training, and AI integration. Overall, CEUS complements other imaging methods and aids precision medicine in liver cancer management.

Cancers doi: 10.20517/2394-5079.2025.106

Authors: Ben Brown,Wen Yuan Chung,John Isherwood

Hepatocellular carcinoma remains a leading cause of cancer-related mortality worldwide. Despite advances in surgical and systemic therapies, recurrence rates remain high, and translational models for therapeutic testing are limited. This review explores the evolving role of ex vivo liver perfusion (EVLP) as a translational platform in hepatoma research, highlighting its applications in tumour modelling, therapeutic testing, and biomarker discovery. A narrative synthesis of recent literature was performed, focusing on EVLP modalities such as normothermic machine perfusion, hypothermic oxygenated perfusion, split-liver perfusion, and segmental perfusion of resected tumour-bearing tissue. EVLP preserves hepatic architecture and metabolic function, enabling real-time study of tumour microenvironments, pharmacological responses, and recurrence mechanisms. Segmental perfusion provides an ethically viable translational model. Overall, EVLP represents a transformative tool in hepatobiliary oncology, bridging the gap between in vitro models and clinical practice, enhancing mechanistic understanding, and accelerating therapeutic innovation.

Cancers doi: 10.20517/2394-5079.2025.42

Authors: Francesco Tovoli,Laura Crocetti,Chiara Mazzarelli,Francesco Giuseppe Foschi,Raffaella Tortora,Martina Gambato,Alessandro Vitale,

The therapeutic landscape of hepatocellular carcinoma (HCC) is undergoing a substantial transformation driven by advances in systemic therapies and locoregional treatments. High response rates observed with immune checkpoint inhibitors and combination regimens have opened the door to conversion therapy. Initially unresectable or non-curable patients can achieve a tumour downsizing to access potentially curative options such as surgery, ablation, or transplantation. This evolving strategy is framed within the concept of the converse therapeutic hierarchy, which promotes a dynamic, response-guided approach. In this model, every treatment is no longer a terminal option but a potential gateway to curative interventions. This review explores the clinical rationale and current evidence supporting conversion therapy in HCC, detailing systemic regimens, transarterial and percutaneous treatments, and their integration into multimodal strategies. Emphasis is placed on response-guided treatment reassessment, perioperative immunotherapy, and the potential of tailored sequencing to redefine clinical practice in HCC. Barriers such as biological heterogeneity, the lack of predictive biomarkers, and organisational gaps in multidisciplinary coordination remain significant. At the same time, improvements in systemic efficacy, advances in locoregional techniques, and new evidence from real-world data point toward a future in which therapeutic intent is no longer fixed but can evolve according to patient response. Conversion therapy, once aspirational, is becoming a realistic and strategic objective in modern HCC care.

Cancers doi: 10.20517/2394-5079.2025.52

Authors: Diyu Chen,Guangming Xu,Aiqing Fan,Yichao Bu,Yuan Fang,Guiqi Zhu,Xiutao Fu,Weiren Liu,Zhenbin Ding,Jian Zhou,Jia Fan,Yinghong Shi,Zheng Tang

Aim: Aberrant metabolism represents a hallmark feature of malignancies, which is crucial for facilitating adenosine triphosphate (ATP) production and biosynthesis of macromolecules that sustain cell proliferation, differentiation, and survival. In the context of tumorigenesis, fatty acids (FAs) have garnered substantial attention due to their dual role as secondary messengers and energy substrates. Notably, the pivotal role of FA metabolism in hepatocellular carcinoma (HCC) progression has been extensively explored. Therefore, this study aims to investigate the contributions of FA metabolism in the immunotherapy of HCC, which remain undefined.

Methods: We analyzed messenger RNA expression and genetic alterations of regulators of FA metabolism from public HCC datasets. Based on their FA metabolism profiles, patients were classified into two distinct molecular subtypes: cluster A and cluster B. Using subtype-derived differentially expressed genes, we established an unsupervised FA_score algorithm. Immune infiltration analysis and prognostic screening of 2,484 immune genes were integrated to develop a risk model, ultimately classifying patients into four integrated subtypes: mixed index (MI)-1 to MI-4.

Result: Cluster B exhibited significantly worse overall survival than cluster A. Higher FA_score correlated with shorter survival and increased infiltration of immunosuppressive cells. The MI-2 subgroup showed abundant CD4+ T cells, myeloid-derived suppressor cells, and regulatory T cells, indicating strong immunosuppression and poor prognosis, suggesting limited benefit from immunotherapy.

Conclusion: We developed a novel classification system integrating FA metabolism and immune features. The MI-2 subtype is characterized by immunosuppression and poor outcomes, highlighting the clinical relevance of FA metabolic patterns in shaping the immune microenvironment and guiding personalized treatment in HCC.

Cancers doi: 10.20517/2394-5079.2025.57

Authors: Meng Li,Weihua Song,Yichi Wu,Haiping Lin,Wangrui Liu,Jiachang Chi

Hepatocellular carcinoma (HCC) arises in a cirrhotic, tolerogenic liver and within a heterogeneous tumor microenvironment (TME) that constrains the efficacy of single-agent systemic therapy. Although immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs have enhanced results, clinicians still lack a mechanistic framework to match specific combinations and locoregional therapies to distinct TME states or disease stages. Here, we synthesize late-phase clinical trial data and experimental studies to link three dominant TME phenotypes - inflamed, immune excluded and immune desert - to first-line ICI-based regimens, including atezolizumab-bevacizumab, durvalumab-tremelimumab, nivolumab-ipilimumab and tyrosine kinase inhibitor-ICI combinations. We outline how the vascular endothelial growth factor (VEGF)-immunity axis, immunogenic cell death after transarterial chemoembolization (TACE), ablation and radiotherapy, and cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING)-driven type I interferon signaling jointly rewire the TME and underpin the emerging “TACE-plus” standard (TACE + ICI + anti-VEGF therapy) in selected intermediate-stage HCC. We then integrate high response-rate regimens into practical algorithms for conversion and neoadjuvant therapy, cirrhosis-specific toxicity management and post-progression sequencing after ICI- or TACE-based treatment. Finally, we map next-generation approaches - Glypican-3-directed chimeric antigen receptor T-cell (CAR-T)/natural killer (NK)/tumor-infiltrating lymphocyte (TIL) products, novel checkpoints such as T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), STING agonists, and personalized neoantigen vaccines - onto putative TME states. We further highlight biomarker priorities, including β-catenin-mediated immune exclusion, angiogenic and interferon signatures, circulating tumor DNA and epigenetic readouts, and the gut-liver axis. A TME-anchored view of HCC provides a rational basis for integrating systemic and locoregional therapies, expanding curative opportunities and designing phenotype-enriched trials.

Cancers doi: 10.20517/2394-5079.2025.69

Authors: Man Kit Christopher Chu,Man Tong

Chimeric antigen receptor-natural killer (CAR-NK) therapy represents an emerging new direction in fighting against cancer. In recent years, it has attracted significant attention, largely due to its notable safety advantages over CAR-T cell therapy and its potential for reduced side effects. In this article, we will review the recent preclinical advances and translational challenges in CAR-NK therapy for the treatment of hepatocellular carcinoma (HCC). Several preclinical studies have successfully demonstrated that targeting HCC-associated tumor antigens such as glypican-3 and cluster of differentiation 147 (CD147) could exert a strong anti-tumor efficacy. However, only a few studies have entered the clinical stage, with none having progressed to late-phase trials. The clinical translation of CAR-NK in HCC is mainly hindered by significant challenges, including the immunosuppressive tumor microenvironment, inefficient tumor trafficking, tumor heterogeneity, and poor persistence of infused cells. To overcome these barriers, researchers have been exploring different innovative strategies such as disrupting the transforming growth factor-β signaling, engineering homing chemokine receptors, developing multi-specific CARs, and enhancing persistence with cytokine support (e.g., interleukin-15). Further ongoing research is important to optimize the CAR constructs and identify effective combination approaches to enhance the overall treatment efficacy.